Interpretive Summary: The clavicipitalean fungi are numerous and highly successful antagonists, primarily of the Panicoideae subfamily of grasses, some of which are mutualistic in their association with plants. The Neotyphodium grass endophytes are known to increase plant growth rate and herbage yield, reduced insect and mammalian predation, and produce tolerances to several abiotic environmental stresses. At the evolutionary levels two broad groups of clavicipitalean fungi developed, therefore varying degree of mutualism might have co-evolved amount both groups. The finding of similar classes of secondary metabolites in both groups strengthens this hypothesis. In addition to chemical co-evolutionary evidence, there is ample evidence to suggest common origins for most clavicipitalean fungi, including molecular and genetic evidence, suggesting that other similarities within this family might exist. Finally, endophytes are also being exploited for their future uses that are based on endophytic delivery mechanisms, i.e., surrogate transformation or paratransgenesis. The information presented here is intended to provide the basis for more detailed discussions based on rigorous research results that will provide the basis for understanding the unique habit of these biotrophic mutualistic fungi of grasses.